The present project addresses two main goals: 1) Discovering new pathways involved in mammary tumor progression, particularly those related to the loss of hormone-dependency; and 2) determine the events that initiate the cascades that trigger programmed mammary cell death during mammary gland involution. Understanding what determines the neoplastic-cell lack of response to the regulatory controls for cell proliferation and death is the main goal for experimental oncology. In the case of mammary cells, one of the main controls for proliferation and differentiation resides in the action of pregnancy-related hormones. Determine new genes and pathways that release the mammary epithelial cells from such a control is a fundamental issue in the fight against breast cancer. A particular aspect of this process will be focused in our studies: the fast and aggressive behavior of tumors that resume growth after long periods of dormancy. Although a relevant issue in the treatment of cancer patients, there have not been too many cellular or molecular approaches to this issue. Our studies will be carried out using new MMTV variants that induce pregnancy-dependent tumors that progress to a hormone-independent behavior. Using the Inverse PCR technique, the MMTV sequences will provide us a molecular tag for cloning host genomic regions that, when altered, contribute to tumor progression. It has been proposed that stimuli that trigger apoptosis in normal ceils, would fail in neoplastic tissue, the mammary gland, the process by which the lactating gland goes back to a virgin-like state is known as mammary involution. This process takes place after each lactation period and involves a very important reduction, by apoptosis, of the mammary alveolar epithelium. The signaling pathways that become activated in the mammary secretory cells right after weaning have received a lot of attention in the scientific community during the last years. However, the very early causes that determine the initiation of this process remain unknown. The purpose of the experiments described in our project is to study these early events to determine how the lack of suckling induces mammary cell death. This issue will be approached by in rive as well as in vitro experiments. In addition, we will focus in determining whether neoplastic cells show alteration in the signaling pathways that lead to mammary epithelium cell death and whether that would be relevant during tumor progression.